This study assessed the antiviral efficacy and safety of tenofovir disoproxil fumarate (TDF) for up to 12 months in Korean treatment-naïve chronic hepatitis B (CHB) patients.
A total of 411 treatment-naïve CHB patients who had been treated with TDF for at least 3 months (median 5.6) were consecutively enrolled. Clinical, biochemical, virological parameters and treatment adherence were routinely assessed every 3 months.
The median age was 51.3 years, 63.0% of the patients were male, 49.6% were HBeAg (+), and 210 patients had liver cirrhosis. The median baseline HBV DNA was 5.98 (SD 1.68) log10 IU/mL. Among the patients completing week 48, 83.3% had a complete virologic response (CVR, <12 IU/mL by HBV PCR assay), and 88.2% had normalized levels of alanine aminotransferase (ALT). The cumulative probabilities of CVR at 3, 6, 9 and 12 months were 22.8%, 53.1%, 69.3% and 85.0%. During the follow-up period, 9.8% patients achieved HBeAg loss and 7.8% patients achieved HBeAg seroconversion. There was no virological breakthrough after initiating TDF. The most common TDF-related adverse event was gastrointestinal upset, and three patients discontinued TDF therapy. However, no serious life-threatening side effect was noted.
In a clinical practice setting, TDF was safe and highly effective when administered for 12 months to Korean treatment-naïve CHB patients.
Hepatitis B virus (HBV) infection is a leading cause of chronic hepatitis, liver cirrhosis and hepatocellular carcinoma (HCC). It has affected over 400 million people worldwide.
In the past, lamivudine (LAM) was used extensively worldwide to treat HBV due to its relatively low cost (available generically in some countries) and favorable tolerability.
Although preferred treatments may vary among countries and regions, and are dependent on the HBV genotypes that are prevalent in the region, present CHB treatment guidelines now recommend highly potent drugs, such as tenofovir disoproxil fumarate (TDF), along with entecavir as first-line therapeutic agents.
TDF, an analogue of adenosine 50-monophosphate, suppresses viral genome replication by inhibiting HBV DNA polymerase activity via competition with the natural substrate.
We included consecutive naïve CHB patients who started TDF at 300 mg daily for at least 3 months in Severance Hospital, Seoul, Korea from December 2012 to December 2013. These patients were identified using the Severance Hospital Liver Disease Cohort Registry (SOLID CORE), which is an internal web-based electronic medical record that encompasses CHB patients treated with antiviral therapy at the Severance Hospital, Yonsei University College of Medicine. The inclusion criteria for this study were age ≥20 years, serum hepatitis B virus surface antigen present ≥ 6 months, serum GFR 50 > mL/min/1.73 m2, more than 3 month treatment with TDF, and therapy naïve hepatitis B patient, defined as patients naïve to TDF who had no other antiviral therapy, such as interferon and other nucleosides, for at least 6 months prior to TDF therapy. Exclusion criteria were treatment with immunomodulatory drugs, current corticosteroid usage, coinfection with hepatitis C and/or D virus or HIV, and serious concurrent medical illness. All patients' laboratory tests at baseline and every 3 months from the starting point were analyzed. All patients were followed up regularly, and measurements were taken of HBV DNA, HBV serology, liver biochemistry and renal function, along with HCC surveillance and assessment of drug compliance. The patients' follow-up period ranged from 3 to 12 month (median 5.6). This study was approved by the local institutional review board and conducted in accordance with the principles set forth in the Declaration of Helsinki.
The primary end point of this study was complete virological response (CVR), which was defined as HBV DNA < 12 IU/mL (lower limit of detection) at any point during therapy. Secondary end points included biochemical response, mean decrease of HBV DNA titer, mean decrease in the Child-Pugh score in patients with decompensated liver cirrhosis, and HBeAg loss or seroconversion during the on-treatment follow up period. An on-treatment ALT flare was defined as an increase of 5x ALT ≥ upper limit of normal (ULN; 46 IU/L) at any time during therapy. Liver cirrhosis was diagnosed based on clinical findings, ultrasonographic findings of a blunted, nodular liver edge accompanied by splenomegaly (>10 cm) with a low platelet count (< 100,000/µL), and/or by pathologic confirmation.
Microsoft Excel 2010 software (Microsoft, Seattle, WA, USA) was used for the database, and all statistical analyses were performed using SPSS version 18.0 (SPSS Inc., Chicago, IL). Continuous variables were summarized as the median (range) or mean ± SD. Cumulative probabilities were estimated using Kaplan-Meier analysis and continuous variables were compared using the t-test.
A total of 1487 patients started TDF between December 2012 and December 2013 at the Severance Hospital, Yonsei University College of Medicine. Among them, 37 patients were treated with primary prophylactic TDF therapy and 9 had a serum GFR 50 < mL/min/1.73 m2. 761 patients were on antiviral therapy immediately before changing to TDF and 165 patients were treated with TDF and another antiviral agent. Another 104 patients had TDF treatment for less than 3 month or were lost during the follow-up period. As a result, a total of 411 patients with naïve CHB were enrolled (
The proportion of patients with CVR is shown in
The proportion of patients with biochemical response is shown in
The proportion of patients achieving HBeAg loss was observed in 20 patients (9.8%), and seroconversion in 16 out of 204 (7.8%) patients, after median treatment duration of 6 months. Sixty three (15.3%) patients had decompensated liver cirrhosis, with a baseline mean Child-Pugh score in these patients were 7.03 (± 2.15 SD). Follow up mean score declined to a level of 6.95, 6.62, 6.12, and 6.06 at month 3, 6, 9 and 12.
The safety and tolerability profiles of TDF are shown in
Traditional treatment for chronic hepatitis B aims to normalize ALT, decrease HBV DNA titer, HBeAg clearance or seroconversion to HBeAg negativity, and improve liver histology. However, updates in the management of chronic hepatitis B increasingly emphasize a reduced HBV DNA titer as a better indication of treatment response, since it is associated with a decreased risk of development of liver cirrhosis or HCC as well as other liver-related events.
In this "real-life" study, we have demonstrated that TDF as an initial therapy for naïve CHB patients was associated with favorable virological and biochemical response rates. This favorable treatment result was equally noted in the study population regardless of HBeAg serostatus and liver cirrhosis status, which is comparable to that of previous studies.
Additionally, our data showed that TDF treatment in decompensated liver cirrhosis was associated with improvement in the Child-Pugh score over time.
No antiviral resistance was observed in our study, consistent with the results of previous studies, which constitutes a distinct advantage over other antiviral agents.
TDF was generally well tolerated in this study, only with a few discontinuations due to adverse events and no life-threatening adverse events. The overall safety profile of TDF in this study was similar to that of previous reports,
One major strength of this study is that it was conducted in Korea, where CHB infection is endemic. Several previous studies have demonstrated the efficacy and safety of TDF;
This study had several limitations. First, its retrospective nature affected the collection of data and analysis of possible confounding factors. However, this study was a retrospective evaluation of a prospectively collected database, the Severance Hospital Liver Disease Cohort Registry (SOLID CORE). Therefore, the study included consecutive patients who received TDF and was intended to examine clinical outcomes in a "real-life" clinical setting.
In summary, this is the first study to provide 12-month data on the efficacy and safety of TDF in naïve CHB patients in Korea. TDF is a potent and safe drug for treatment of naïve CHB patients, but due to its higher cost compared to other antiviral agents, it may not be feasible to use for an extended period. Additional studies with larger sample sizes are required to evaluate the response rates, efficacy, incidence of various adverse events, and decrease in liver-related events following HBV DNA suppression.
We thank Dong-Su Jang (Medical Illustrator, Medical Research Support Section, Yonsei University College of Medicine, Seoul, Korea) for assistance with the figures.
No potential conflict of interest relevant to this article was reported.
tenofovir disoproxil fumarate
chronic hepatitis B
lamivudine
complete virological response
hepatocellular carcinoma
hepatitis B virus
aspartate aminotransferase
alanine aminotransferase
Cumulative probability of complete virological response through TDF treatment.
Mean change HBV DNA titer through TDF treatment. LLOQ, lower limit of quantification.
Baseline characteristics of the subjects
Characteristic | Value |
---|---|
Total patients | 411 |
Age, years | 52 (22-86) |
Male sex | 259 (63.0%) |
Liver cirrhosis | 210 (51%) |
HBeAg positive | 204 (49.6%) |
HBV DNA, log IU/mL | 5.98 (1.68) |
AST, IU/L | 103.7 (194.0) |
ALT, IU/L | 126.3 (196.0) |
BUN, mg/dL | 13.7 (7.2) |
Cr, mg/dL | 0.8 (0.3) |
GFR, mL/min/1.73 m² (mean± SD) | 85.7 (10.0) |
Variables are expressed as median (range), mean (SD) or n (%).
AST, aspartate aminotransferase; ALT, alanine aminotransferase; Cr, creatinine; BUN, blood urea nitrogen; GFR, glomerular filtration rate.
Proportion of patients with virological responses (undetectable HBV DNA
Patient's response | 3 month | 6 month | 9 month | 12 month |
---|---|---|---|---|
Total, n (%) | 94/411 (22.8) | 176/281 (62.6) | 151/188 (80.3) | 100/120 (83.3) |
HBeAg (+), n (%) | 15/204 (7.3) | 50/128 (39.0) | 53/79 (67.0) | 43/60 (71.6) |
HBeAg (-), n (%) | 79/207 (38.1) | 126/153 (82.3) | 98/109 (89.9) | 57/60 (95) |
Liver cirrhosis, n (%) | 51/210 (24.2) | 94/137 (68.6) | 81/96 (84.3) | 50/56 (89.2) |
Non cirrhosis, n (%) | 43/201 (21.3) | 82/144 (56.9) | 70/92 (76.0) | 50/64 (78.1) |
HBV, hepatitis B virus; HBeAg, hepatitis e antigen.
The HBV DNA reference range was ≤12 IU/mL.
Proportion of patients with biochemical responses (ALT normalizationa) according to HBeAg and liver cirrhosis status
Patient's response | 3 month | 6 month | 9 month | 12 month |
---|---|---|---|---|
Total, n (%) | 281/411 (68.3) | 214/272 (78.6) | 121/155 (78) | 83/94 (88.2) |
HBeAg (+), n (%) | 132/204 (64.7) | 106/136 (77.9) | 52/68 (76.4) | 44/49 (89.7) |
HBeAg (-), n (%) | 149/207 (71.9) | 108/136 (79.4) | 69/87 (79.3) | 39/45 (86.6) |
Liver cirrhosis, n (%) | 146/210 (69.5) | 98/135 (72.5) | 56/78 (71.7) | 38/43 (88.3) |
Non cirrhosis, n (%) | 135/201 (67.1) | 116/138 (84.6) | 65/76 (85.5) | 45/51 (88.2) |
The alanine aminotransferase (ALT) reference range was ≤46 IU/L.
Incidence of adverse events in the TDF treated population
Adverse events | n (%) of patients |
---|---|
Gastrointestinal | 57 (13.8%) |
AST and/or ALT elevation (x5 ≥ULN) | 17 (4.1%) |
Abdominal discomfort | 15 (3.6%) |
Nausea | 11 (2.6%) |
Fatigue | 8 (1.9%) |
Poor oral intake | 6 (1.4%) |
Renal | |
Cr elevation (≥0.2 mg/dL) | 12 (2.9%) |
Other | |
Skin rash | 2 (0.4%) |
Stop TDF for adverse event | 3 (0.7%) |
AST, aspartate aminotransferase; TDF, tenofovir disoproxil fumaratea.